Estrogens are commonly used in hormone replacement therapy for the treatment of post-menopausal symptoms and osteoporosis. Many women, however, continue to experience symptoms after estrogen monotherapy. The beneficial effects of androgens on the post-menopausal woman's physical and emotional well-being are only recently being recognized. Several clinical studies have established the basis of combined estrogen-androgen therapy. In a series of double-blind, controlled studies at McGill University, it was noted that patients on estrogen-androgen combination therapy had higher daily scores of well-being, energy level, and quality of sleep than patients on estrogen replacement therapy (ERT) alone. The authors also reported a beneficial effect of estrogen-androgen therapy on sexual function, and no adverse effects on lipids.
Androgens are the hormones of choice in helping restore lost sex drive, although estrogens alone may help some women. Several reports in the literature establish the beneficial effects of androgen therapy on sexual function. This is particularly important in younger, surgically post-menopausal women, who have increased motivational aspect of sexual behavior (such as desire and arousal) when treated with parenteral androgen, either alone or in combination with an estrogen, compared to estrogen alone or placebo. Justification for the addition of androgens to ERT for the prevention of osteoporosis is also found in the literature.
While the benefits of adding an androgen to an ERT regimen are well established, the dosage forms available for androgen therapy or estrogen-androgen combination therapy leave much to be desired. In particular, none of these modalities can produce serum testosterone levels that remain within normal physiological range on a daily basis. The androgens most available for clinical use are not typically the native testosterone; synthetic androgens are commonly used (methyl testosterone, for example which is known to be hepatotoxic). Native testosterone is available as implantable pellets; however this system requires an invasive administration and does not produce a stable physiological hormonal state. Injectable testosterone esters such as testosterone propionate and the long-acting testosterone enanthate produce marked supraphysiological fluctuations in hormone levels. The non- and supraphysiological nature of the current androgen replacement products are responsible for the signs and symptoms of excess androgen effect frequently seen with their use. These include virilizing symptoms such as hirsutism, male pattern baldness, voice lowering and clitoromegaly; disturbances in ovulation and menstrual function; acne and oily skin; and breast tenderness, fluid retention, irritability and depression. These problems are also present with estrogen-androgen products currently on the market. A modality producing physiological levels of testosterone and its metabolites, with or without estrogen, would have significant therapeutic benefits over existing androgen replacement products.
Many articles and patents have suggested or reported transdermal administration of testosterone. In general, these publications have focused on providing testosterone therapy to men to treat conditions such as male hypogonadism, anemia, and male osteoporosis. Much of this literature concludes that testosterone, without some form of permeation enhancement, does not pass through non-scrotal skin at practical fluxes. Most recently, U.S. Pat. No. 5,152,997 describes the transdermal administration of testosterone to males through non-scrotal skin under conditions (subsaturation concentrations of testosterone in the skin patch; coadministration of skin permeation enhancers) that provide practical flux levels. This literature is virtually silent on the subject of providing testosterone or combined testosterone/estrogen replacement therapy to women transdermally.